Dobbelstein, Matthias

[["dc.bibliographiccitation.artnumber","110879"],["dc.bibliographiccitation.issue","9"],["dc.bibliographiccitation.journal","Cell Reports"],["dc.bibliographiccitation.volume","39"],["dc.contributor.author","Giansanti, Celeste"],["dc.contributor.author","Manzini, Valentina"],["dc.contributor.author","Dickmanns, Antje"],["dc.contributor.author","Dickmanns, Achim"],["dc.contributor.author","Palumbieri, Maria Dilia"],["dc.contributor.author","Sanchi, Andrea"],["dc.contributor.author","Kienle, Simon Maria"],["dc.contributor.author","Rieth, Sonja"],["dc.contributor.author","Scheffner, Martin"],["dc.contributor.author","Lopes, Massimo"],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2022-07-01T07:35:41Z"],["dc.date.available","2022-07-01T07:35:41Z"],["dc.date.issued","2022"],["dc.description.abstract","The MDM2 oncoprotein antagonizes the tumor suppressor p53 by physical interaction and ubiquitination.\r\nHowever, it also sustains the progression of DNA replication forks, even in the absence of functional p53.\r\nHere, we show that MDM2 binds, inhibits, ubiquitinates, and destabilizes poly(ADP-ribose) polymerase 1\r\n(PARP1). When cellular MDM2 levels are increased, this leads to accelerated progression of DNA replication\r\nforks, much like pharmacological inhibition of PARP1. Conversely, overexpressed PARP1 restores normal\r\nfork progression despite elevated MDM2. Strikingly, MDM2 profoundly reduces the frequency of fork\r\nreversal, revealed as four-way junctions through electron microscopy. Depletion of RECQ1 or the primase/\r\npolymerase (PRIMPOL) reverses the MDM2-mediated acceleration of the nascent DNA elongation rate.\r\nMDM2 also increases the occurrence of micronuclei, and it exacerbates camptothecin-induced cell death.\r\nIn conclusion, high MDM2 levels phenocopy PARP inhibition in modulation of fork restart, representing a\r\npotential vulnerability of cancer cells."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2022"],["dc.identifier.doi","10.1016/j.celrep.2022.110879"],["dc.identifier.pii","S2211124722006544"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/112236"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-581"],["dc.relation.issn","2211-1247"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://www.elsevier.com/tdm/userlicense/1.0/"],["dc.title","MDM2 binds and ubiquitinates PARP1 to enhance DNA replication fork progression"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","S2589004222005636"],["dc.bibliographiccitation.firstpage","104293"],["dc.bibliographiccitation.issue","5"],["dc.bibliographiccitation.journal","iScience"],["dc.bibliographiccitation.volume","25"],["dc.contributor.author","Stegmann, Kim M."],["dc.contributor.author","Dickmanns, Antje"],["dc.contributor.author","Heinen, Natalie"],["dc.contributor.author","Blaurock, Claudia"],["dc.contributor.author","Karrasch, Tim"],["dc.contributor.author","Breithaupt, Angele"],["dc.contributor.author","Klopfleisch, Robert"],["dc.contributor.author","Uhlig, Nadja"],["dc.contributor.author","Eberlein, Valentina"],["dc.contributor.author","Issmail, Leila"],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2022-06-01T09:40:16Z"],["dc.date.available","2022-06-01T09:40:16Z"],["dc.date.issued","2022"],["dc.description.sponsorship","Open-Access-Publikationsfonds 2022"],["dc.identifier.doi","10.1016/j.isci.2022.104293"],["dc.identifier.pii","S2589004222005636"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/108685"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-572"],["dc.relation.issn","2589-0042"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://www.elsevier.com/tdm/userlicense/1.0/"],["dc.title","Inhibitors of dihydroorotate dehydrogenase cooperate with molnupiravir and N4-hydroxycytidine to suppress SARS-CoV-2 replication"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","S0168170221001763"],["dc.bibliographiccitation.firstpage","198469"],["dc.bibliographiccitation.journal","Virus Research"],["dc.bibliographiccitation.volume","302"],["dc.contributor.author","Stegmann, Kim M."],["dc.contributor.author","Dickmanns, Antje"],["dc.contributor.author","Gerber, Sabrina"],["dc.contributor.author","Nikolova, Vella"],["dc.contributor.author","Klemke, Luisa"],["dc.contributor.author","Manzini, Valentina"],["dc.contributor.author","Schlösser, Denise"],["dc.contributor.author","Bierwirth, Cathrin"],["dc.contributor.author","Freund, Julia"],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2021-07-05T15:00:26Z"],["dc.date.available","2021-07-05T15:00:26Z"],["dc.date.issued","2021"],["dc.identifier.doi","10.1016/j.virusres.2021.198469"],["dc.identifier.pii","S0168170221001763"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/87826"],["dc.language.iso","en"],["dc.notes.intern","DOI Import DOI-Import GROB-441"],["dc.relation.issn","0168-1702"],["dc.title","The folate antagonist methotrexate diminishes replication of the coronavirus SARS-CoV-2 and enhances the antiviral efficacy of remdesivir in cell culture models"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","68"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Molecular Cell"],["dc.bibliographiccitation.lastpage","83"],["dc.bibliographiccitation.volume","61"],["dc.contributor.author","Wienken, Magdalena"],["dc.contributor.author","Dickmanns, Antje"],["dc.contributor.author","Nemajerova, Alice"],["dc.contributor.author","Kramer, Daniela"],["dc.contributor.author","Najafova, Zeynab"],["dc.contributor.author","Weiss, Miriam"],["dc.contributor.author","Karpiuk, Oleksandra"],["dc.contributor.author","Kassem, Moustapha"],["dc.contributor.author","Zhang, Y."],["dc.contributor.author","Lozano, Guillermina"],["dc.contributor.author","Johnsen, Steven A."],["dc.contributor.author","Moll, Ute M."],["dc.contributor.author","Zhang, X."],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2018-11-07T10:19:27Z"],["dc.date.available","2018-11-07T10:19:27Z"],["dc.date.issued","2016"],["dc.description.abstract","The MDM2 oncoprotein ubiquitinates and antagonizes p53 but may also carry out p53-independent functions. Here we report that MDM2 is required for the efficient generation of induced pluripotent stem cells (iPSCs) from murine embryonic fibroblasts, in the absence of p53. Similarly, MDM2 depletion in the context of p53 deficiency also promoted the differentiation of human mesenchymal stem cells and diminished clonogenic survival of cancer cells. Most of the MDM2-controlled genes also responded to the inactivation of the Polycomb Repressor Complex 2 (PRC2) and its catalytic component EZH2. MDM2 physically associated with EZH2 on chromatin, enhancing the trimethylation of histone 3 at lysine 27 and the ubiquitination of histone 2A at lysine 119 (H2AK119) at its target genes. Removing MDM2 simultaneously with the H2AK119 E3 ligase Ring1B/RNF2 further induced these genes and synthetically arrested cell proliferation. In conclusion, MDM2 supports the Polycomb-mediated repression of lineage-specific genes, independent of p53."],["dc.identifier.doi","10.1016/j.molcel.2015.12.008"],["dc.identifier.isi","000372324500007"],["dc.identifier.pmid","26748827"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/41663"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Cell Press"],["dc.relation.issn","1097-4164"],["dc.relation.issn","1097-2765"],["dc.title","MDM2 Associates with Polycomb Repressor Complex 2 and Enhances Stemness-Promoting Chromatin Modifications Independent of p53"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","580"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","Cell Cycle"],["dc.bibliographiccitation.lastpage","587"],["dc.bibliographiccitation.volume","9"],["dc.contributor.author","Drewelus, Isabella"],["dc.contributor.author","Göpfert, Constanze"],["dc.contributor.author","Hippel, Cathrin"],["dc.contributor.author","Dickmanns, Antje"],["dc.contributor.author","Damianitsch, Katharina"],["dc.contributor.author","Pieler, Tomas"],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2022-03-01T11:44:31Z"],["dc.date.available","2022-03-01T11:44:31Z"],["dc.date.issued","2010"],["dc.description.abstract","The p53 homologue p63/TP73L is required for the proper development of squamous epithelia, mammary glands and limb buds, with some of these tissues also displaying strong canonical Wnt signalling activity. It was previously suggested that Delta Np63 alpha, the predominant isoform of p63 in epithelia, positively regulates beta-Catenin through inhibition of GSK3 beta. Results reported in this communication show that, upon transient overexpression, Delta Np63 alpha indeed promotes Wnt-inducible reporter gene activity in human cells, as well as secondary axis formation in Xenopus embryos. However, in apparent contradiction to these observations, siRNA-mediated knockdown of endogenous p63 equally enhanced the expression of Wnt-responsive genes. While p63 knockdown did not detectably affect beta-Catenin levels or phosphorylation, Delta Np63 alpha was found in a complex with members of the TCF/LEF family of Wnt-responsive transcription factors. On the basis of these findings, we propose that Delta Np63 alpha has a function in recruiting transcriptional repressors to Wnt-responsive genes. Overexpression of p63 may lead to sequestration of such repressors (squelching), resulting in a similar effect like siRNA-mediated removal of p63, i.e., activation of Wnt-responsive genes. The role of p63 as a negative Wnt-regulator thus matches with the frequently observed downregulation of p63 during tumor progression, when cancer cells adopt a more mesenchymal, invasive phenotype."],["dc.identifier.isi","000274140000038"],["dc.identifier.pmid","20107313"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/103040"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-531"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Landes Bioscience"],["dc.relation.eissn","1551-4005"],["dc.relation.issn","1538-4101"],["dc.title","p63 antagonizes Wnt-induced transcription"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","918"],["dc.bibliographiccitation.issue","9"],["dc.bibliographiccitation.journal","Cell Death & Disease"],["dc.bibliographiccitation.volume","9"],["dc.contributor.author","Sriraman, Anusha"],["dc.contributor.author","Dickmanns, Antje"],["dc.contributor.author","Najafova, Zeynab"],["dc.contributor.author","Johnsen, Steven A."],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2019-07-09T11:45:55Z"],["dc.date.available","2019-07-09T11:45:55Z"],["dc.date.issued","2018"],["dc.description.abstract","The genes encoding MDM2 and CDK4 are frequently co-amplified in sarcomas, and inhibitors to both targets are approved or clinically tested for therapy. However, we show that inhibitors of MDM2 and CDK4 antagonize each other in their cytotoxicity towards sarcoma cells. CDK4 inhibition attenuates the induction of p53-responsive genes upon MDM2 inhibition. Moreover, the p53 response was also attenuated when co-depleting MDM2 and CDK4 with siRNA, compared to MDM2 single knockdown. The complexes of p53 and MDM2, as well as CDK4 and Cyclin D1, physically associated with each other, suggesting direct regulation of p53 by CDK4. Interestingly, CDK4 inhibition did not reduce p53 binding or histone acetylation at promoters, but rather attenuated the subsequent recruitment of RNA Polymerase II. Taken together, our results suggest that caution must be used when considering combined CDK4 and MDM2 inhibition for patient treatment. Moreover, they uncover a hitherto unknown role for CDK4 and Cyclin D1 in sustaining p53 activity."],["dc.identifier.doi","10.1038/s41419-018-0968-0"],["dc.identifier.pmid","30206211"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15347"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59339"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation.issn","2041-4889"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject.ddc","610"],["dc.title","CDK4 inhibition diminishes p53 activation by MDM2 antagonists"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","19"],["dc.bibliographiccitation.journal","The EMBO Journal"],["dc.bibliographiccitation.volume","40"],["dc.contributor.affiliation","Güttler, Thomas; 1Department of Cellular Logistics Max Planck Institute for Biophysical Chemistry Göttingen Germany"],["dc.contributor.affiliation","Aksu, Metin; 1Department of Cellular Logistics Max Planck Institute for Biophysical Chemistry Göttingen Germany"],["dc.contributor.affiliation","Dickmanns, Antje; 2Institute of Molecular Oncology GZMB University Medical Center Göttingen Germany"],["dc.contributor.affiliation","Stegmann, Kim M.; 2Institute of Molecular Oncology GZMB University Medical Center Göttingen Germany"],["dc.contributor.affiliation","Gregor, Kathrin; 1Department of Cellular Logistics Max Planck Institute for Biophysical Chemistry Göttingen Germany"],["dc.contributor.affiliation","Rees, Renate; 1Department of Cellular Logistics Max Planck Institute for Biophysical Chemistry Göttingen Germany"],["dc.contributor.affiliation","Taxer, Waltraud; 1Department of Cellular Logistics Max Planck Institute for Biophysical Chemistry Göttingen Germany"],["dc.contributor.affiliation","Rymarenko, Oleh; 1Department of Cellular Logistics Max Planck Institute for Biophysical Chemistry Göttingen Germany"],["dc.contributor.affiliation","Schünemann, Jürgen; 1Department of Cellular Logistics Max Planck Institute for Biophysical Chemistry Göttingen Germany"],["dc.contributor.affiliation","Dienemann, Christian; 3Department of Molecular Biology Max Planck Institute for Biophysical Chemistry Göttingen Germany"],["dc.contributor.affiliation","Gunkel, Philip; 1Department of Cellular Logistics Max Planck Institute for Biophysical Chemistry Göttingen Germany"],["dc.contributor.affiliation","Mussil, Bianka; 1Department of Cellular Logistics Max Planck Institute for Biophysical Chemistry Göttingen Germany"],["dc.contributor.affiliation","Krull, Jens; 1Department of Cellular Logistics Max Planck Institute for Biophysical Chemistry Göttingen Germany"],["dc.contributor.affiliation","Teichmann, Ulrike; 4Animal facility Max Planck Institute for Biophysical Chemistry Göttingen Germany"],["dc.contributor.affiliation","Groß, Uwe; 5Institute of Medical Microbiology and Virology University Medical Center Göttingen Germany"],["dc.contributor.affiliation","Cordes, Volker C; 1Department of Cellular Logistics Max Planck Institute for Biophysical Chemistry Göttingen Germany"],["dc.contributor.author","Güttler, Thomas"],["dc.contributor.author","Aksu, Metin"],["dc.contributor.author","Dickmanns, Antje"],["dc.contributor.author","Stegmann, Kim M."],["dc.contributor.author","Gregor, Kathrin"],["dc.contributor.author","Rees, Renate"],["dc.contributor.author","Taxer, Waltraud"],["dc.contributor.author","Rymarenko, Oleh"],["dc.contributor.author","Schünemann, Jürgen"],["dc.contributor.author","Dienemann, Christian"],["dc.contributor.author","Görlich, Dirk"],["dc.contributor.author","Groß, Uwe"],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2021-09-01T06:38:23Z"],["dc.date.available","2021-09-01T06:38:23Z"],["dc.date.issued","2021"],["dc.date.updated","2022-03-21T10:12:03Z"],["dc.description.abstract","Abstract Monoclonal anti‐SARS‐CoV‐2 immunoglobulins represent a treatment option for COVID‐19. However, their production in mammalian cells is not scalable to meet the global demand. Single‐domain (VHH) antibodies (also called nanobodies) provide an alternative suitable for microbial production. Using alpaca immune libraries against the receptor‐binding domain (RBD) of the SARS‐CoV‐2 Spike protein, we isolated 45 infection‐blocking VHH antibodies. These include nanobodies that can withstand 95°C. The most effective VHH antibody neutralizes SARS‐CoV‐2 at 17–50 pM concentration (0.2–0.7 µg per liter), binds the open and closed states of the Spike, and shows a tight RBD interaction in the X‐ray and cryo‐EM structures. The best VHH trimers neutralize even at 40 ng per liter. We constructed nanobody tandems and identified nanobody monomers that tolerate the K417N/T, E484K, N501Y, and L452R immune‐escape mutations found in the Alpha, Beta, Gamma, Epsilon, Iota, and Delta/Kappa lineages. We also demonstrate neutralization of the Beta strain at low‐picomolar VHH concentrations. We further discovered VHH antibodies that enforce native folding of the RBD in the E. coli cytosol, where its folding normally fails. Such “fold‐promoting” nanobodies may allow for simplified production of vaccines and their adaptation to viral escape‐mutations."],["dc.description.abstract","SYNOPSIS image Effective treatment options for SARS‐CoV‐2 infections/COVID‐19 are still sparse. This study revealed highly potent therapeutic nanobodies/single‐domain (VHH) antibodies that neutralize SARS‐CoV‐2 and its emerging immune‐escape mutants. Alpaca immune libraries yielded 45 VHHs (of 22 sequence classes) that target two epitopes of the SARS‐CoV‐2 receptor‐binding domain (RBD) and block infection. The lead nanobody monomers are hyperthermostable, bind the RBD with low‐picomolar affinity and neutralize the virus at a concentration of 0.2–0.7 micrograms per liter (IC99+). Enhancement of the nanobodies' avidity by trimerization with the collagen XVIII NC1 domain yields neutralizers that block SARS‐CoV‐2 at concentrations as low as 40 nanograms per liter (IC99+). Clinical candidates include nanobody trimers, tandem fusions and monomers that bind the major SARS‐CoV‐2 immune‐escape mutants with high affinity and neutralize, e.g., the Beta/B.1.351 variant. “Fold‐promoting” nanobodies assist de novo protein folding in the E. coli cytosol, as demonstrated with nanobody⋅RBD complexes."],["dc.description.abstract","Single‐domain camelid antibodies that neutralize a range of common and emerging immune‐escape mutant strains of SARS‐CoV‐2 may constitute an easily‐producible option for treatment of COVID‐19 patients. image"],["dc.description.sponsorship","Max Planck Society http://dx.doi.org/10.13039/501100004189"],["dc.description.sponsorship","Max Planck Foundation"],["dc.identifier.doi","10.15252/embj.2021107985"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/88920"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-455"],["dc.relation.eissn","1460-2075"],["dc.relation.issn","0261-4189"],["dc.rights","This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited."],["dc.title","Neutralization of SARS‐CoV‐2 by highly potent, hyperthermostable, and mutation‐tolerant nanobodies"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","5765"],["dc.bibliographiccitation.issue","11"],["dc.bibliographiccitation.journal","Journal of Clinical Investigation"],["dc.bibliographiccitation.lastpage","5781"],["dc.bibliographiccitation.volume","130"],["dc.contributor.author","Müller, Anne"],["dc.contributor.author","Dickmanns, Antje"],["dc.contributor.author","Resch, Claudia"],["dc.contributor.author","Schäkel, Knut"],["dc.contributor.author","Hailfinger, Stephan"],["dc.contributor.author","Dobbelstein, Matthias"],["dc.contributor.author","Schulze-Osthoff, Klaus"],["dc.contributor.author","Kramer, Daniela"],["dc.date.accessioned","2021-04-14T08:31:22Z"],["dc.date.available","2021-04-14T08:31:22Z"],["dc.date.issued","2020"],["dc.identifier.doi","10.1172/JCI134217"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/83571"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-399"],["dc.relation.eissn","1558-8238"],["dc.relation.issn","0021-9738"],["dc.title","The CDK4/6-EZH2 pathway is a potential therapeutic target for psoriasis"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]